RESUMEN
Piroplasmids and Hepatozoon spp. Are apicomplexan protozoa that may cause disease in several canid species. The present study aimed to expand the knowledge on the diversity of piroplasmids and Hepatozoon in crab-eating foxes (Cerdocyon thous; n = 12) sampled in the Pantanal of Mato Grosso do Sul State, central-western Brazil. PCR assays based on the 18S rRNA were used as screening. Three (25%) and 11 (91.7%) were positive for piroplasmids and Hepatozoon spp., respectively. Co-infection was found in three C. thous. Phylogenetic analyses based on the near-complete 18S rRNA, cox-1 and hsp70 genes evidenced the occurrence of a novel of Babesia spp. (namely Babesia pantanalensis nov. sp.) closely related to Rangelia vitalii and Babesia sp. 'Coco'. This finding was supported by the genetic divergence analysis which showed (i) high divergence, ranging from 4.17 to 5.62% for 18 S rRNA, 6.16% for hps70 and 4.91-9.25% for cox-1 and (ii) the genotype network (which displayed sequences separated from the previously described Piroplasmida species by median vectors and several mutational events). Also, phylogenetic analysis based on the 18S rRNA gene of Hepatozoon spp. positioned the sequences obtained herein in a clade phylogenetically related to Hepatozoon sp. 'Curupira 2', Hepatozoon sp. detected in domestic and wild canids from Uruguay and Hepatozoon americanum. The present study described Babesia pantanalensis nov sp. and Hepatozoon closely related to H. americanum in crab-eating foxes from Brazil. Moreover, the coinfection by piroplasmids and Hepatozoon sp. for the first time in crab-eating foxes strongly suggesting that this wild canid species potentially acts as a bio-accumulate of hemoprotozoan in wild environment.
Asunto(s)
Babesia , Babesiosis , Coccidiosis , ADN Protozoario , Genotipo , Filogenia , ARN Ribosómico 18S , Animales , Babesia/genética , Babesia/clasificación , Babesia/aislamiento & purificación , ARN Ribosómico 18S/genética , Babesiosis/parasitología , Babesiosis/epidemiología , Brasil/epidemiología , Coccidiosis/veterinaria , Coccidiosis/parasitología , Coccidiosis/epidemiología , ADN Protozoario/química , ADN Protozoario/aislamiento & purificación , Eucoccidiida/genética , Eucoccidiida/clasificación , Eucoccidiida/aislamiento & purificación , Ciclooxigenasa 1/genética , Reacción en Cadena de la Polimerasa/veterinaria , Proteínas HSP70 de Choque Térmico/genética , Coinfección/veterinaria , Coinfección/parasitología , Zorros/parasitología , Canidae/parasitología , Complejo IV de Transporte de Electrones/genéticaRESUMEN
This study carried out to investigate the anti-inflammatory and antinociceptive effect of tropane alkaloid (EB7) isolated from E. bezerrae. It evaluated the toxicity and possible involvement of ion channels in the antinociceptive effect of EB7, as well as its anti-inflammatory effect in adult zebrafish (Zfa). Docking studies with EB7 and COX-1 and 2 were also performed. The tested doses of EB7 (4, 20 and 40â mg/kg) did not show any toxic effect on Zfa during the 96h of analysis (LD50>40â mg/kg). They did not produce any alteration in the locomotor behavior of the animals. Furthermore, EB7 showed promising pharmacological effects as it prevented the nociceptive behavior induced by hypertonic saline, capsaicin, formalin and acid saline. EB7 had its analgesic effect blocked by amiloride involving the neuromodulation of ASICs in Zfa. In evaluating the anti-inflammatory activity, the edema induced by κ-carrageenan 3.5 % was reduced by the dose of 40â mg/kg of EB7 observed after the fourth hour of analysis, indicating an effect similar to that of ibuprofen. Molecular docking results indicated that EB7 exhibited better affinity energy when compared to ibuprofen control against the two evaluated targets binding at different sites in the cocrystallized COX-1 and 2 inhibitors.
Asunto(s)
Analgésicos , Simulación del Acoplamiento Molecular , Pez Cebra , Animales , Analgésicos/farmacología , Analgésicos/química , Analgésicos/aislamiento & purificación , Tropanos/farmacología , Tropanos/aislamiento & purificación , Tropanos/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Carragenina/farmacología , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 1/metabolismo , Bignoniaceae/química , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Alcaloides/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/química , Canales Iónicos Sensibles al Ácido/metabolismo , Canales Iónicos Sensibles al Ácido/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Estructura MolecularRESUMEN
α-Adrenergic receptors are crucial regulators of vascular hemodynamics and essential pharmacological targets for cardiovascular diseases. With aging, there is an increase in sympathetic activation, which could contribute to the progression of aging-associated cardiovascular dysfunction, including stroke. Nevertheless, there is little information directly associating adrenergic receptor dysfunction in the blood vessels of aged females. This study determined the role of a-adrenergic receptors in carotid dysfunction of senescent female mice (accelerated-senescence prone, SAMP8), compared with a nonsenescent (accelerated-senescence prone, SAMR1). Vasoconstriction to phenylephrine (Phe) was markedly increased in common carotid artery of SAMP8 [area under the curve (AUC), 527 ± 53] compared with SAMR1 (AUC, 334 ± 30, P = 0.006). There were no changes in vascular responses to the vasoconstrictor agent U46619 or the vasodilators acetylcholine (ACh) and sodium nitroprusside (NPS). Hyperactivity to Phe in female SAMP8 was reduced by cyclooxygenase-1 and cyclooxygenase-2 inhibition and associated with augmented ratio of TXA2/PGI2 release (SAMR1, 1.1 ± 0.1 vs. SAMP8, 2.1 ± 0.3, P = 0.007). However, no changes in cyclooxygenase expression were seen in SAMP8 carotids. Selective α1A-receptor antagonism markedly reduced maximal contraction, whereas α1D antagonism induced a minor shift in Phe contraction in SAMP8 carotids. Ligand binding analysis revealed a threefold increase of α-adrenergic receptor density in smooth muscle cells (VSMCs) of SAMP8 vs. SAMR1. Phe rapidly increased intracellular calcium (Cai2+) in VSMCs via the α1A-receptor, with a higher peak in VSMCs from SAMP8. In conclusion, senescence intensifies vasoconstriction mediated by α1A-adrenergic signaling in the carotid of female mice by mechanisms involving increased Cai2+ and release of cyclooxygenase-derived prostanoids.NEW & NOTEWORTHY The present study provides evidence that senescence induces hyperreactivity of α1-adrenoceptor-mediated contraction of the common carotid. Impairment of α1-adrenoceptor responses is linked to increased Ca2+ influx and release of COX-derived vasoconstrictor prostanoids, contributing to carotid dysfunction in the murine model of female senescence (SAMP8). Increased reactivity of the common carotid artery during senescence may lead to morphological and functional changes in arteries of the cerebral microcirculation and contribute to cognitive decline in females. Because the elderly population is growing, elucidating the mechanisms of aging- and sex-associated vascular dysfunction is critical to better direct pharmacological and lifestyle interventions to prevent cardiovascular risk in both sexes.
Asunto(s)
Prostaglandinas , Vasoconstrictores , Anciano , Humanos , Masculino , Ratones , Femenino , Animales , Vasoconstrictores/farmacología , Ciclooxigenasa 1 , Prostaglandinas/metabolismo , Envejecimiento/metabolismo , Fenilefrina/farmacología , Ciclooxigenasa 2RESUMEN
AIMS: Obesity can lead to the loss of the anticontractile properties of perivascular adipose tissue (PVAT). Given that cafeteria (CAF) diet reflects the variety of highly calorie and easily accessible foods in Western societies, contributing to obesity and metabolic disorders, we sought to investigate the impact of CAF diet on PVAT vasoactive profile and the involvement of renin-angiotensin system, oxidative stress, and cyclooxygenase pathway. MAIN METHODS: Male Balb/c mice received standard or CAF diet for 4 weeks. Oral glucose tolerance and insulin sensitivity tests were performed, and fasting serum glucose, cholesterol and triglyceride parameters were determined. Vascular reactivity, fluorescence and immunofluorescence analyzes were carried out in intact thoracic aorta in the presence or absence of PVAT. KEY FINDINGS: CAF diet was effective in inducing obesity and metabolic disorders, as demonstrated by increased body weight gain and adiposity index, hyperlipidemia, hyperglycemia, glucose intolerance and insulin insensitivity. Importantly, CAF diet led to a significant decrease in aortic contractility which was restored in the presence of PVAT, exhibiting therefore a contractile profile. The contractile effect of PVAT was associated with the activation of AT1 receptor, reactive oxygen species, cyclooxygenase-1, thromboxane A2 and prostaglandin E2 receptors. SIGNIFICANCE: These findings suggest that the contractile profile of PVAT involving the renin-angiotensin system activation, reactive oxygen species and cyclooxygenase-1 metabolites may be a protective compensatory adaptive response during early stage of CAF diet-induced obesity as an attempt to restore the impaired vascular contraction observed in the absence of PVAT, contributing to the maintenance of vascular tone.
Asunto(s)
Insulinas , Prostaglandinas , Animales , Ratones , Masculino , Especies Reactivas de Oxígeno/metabolismo , Prostaglandinas/metabolismo , Ciclooxigenasa 1/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Tejido Adiposo/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos BALB C , Glucosa/metabolismo , Tromboxanos/metabolismo , Triglicéridos/metabolismo , Insulinas/metabolismoRESUMEN
Las urgencias odontológicas son, quizá, las razones principales de atención en el consultorio, muchas veces el significado de dolor se encuentra acompañado por inflamación; el uso de antiinflamatorios no esteroideos (AINES) es común en el ejercicio de la odontología por la excelente respuesta analgésica y antiinflamatoria que tiene, por lo que es importante conocer la fisiopatología de la inflamación y el dolor y cómo actúan los AINES, ya que algunos de estos fármacos tienen respuestas adversas y sitios de acción importantes. Los factores de riesgo por inflamación y dolor nos obligan a conocer la variedad de fármacos que no entran en la clasificación de AINES y que tenemos a disposición, hay más opciones para la elección ante la presencia de inflamación por un factor en particular, cada uno de éstos tienen indicaciones y contraindicaciones que conoceremos, lo cual nos ampliará el conocimiento para dar una prescripción ante la presencia de eventos inflamatorios. Se realizó un estudio detallado de artículos bibliográficos de cada tema, los fármacos más usados en odontología son los AINES, hay poco uso y conocimiento de antiinflamatorios que podemos usar en urgencias, el porcentaje de uso de los AINES derivados del ácido propiónico es alto por la excelente respuesta en pacientes y otras veces por el desconocimiento de más opciones (AU)
Dental emergencies are perhaps the main reasons for care in the office, many times the meaning of pain is accompanied by inflammation, the use of non-steroidal anti-inflammatory drugs is common in the practice of dentistry due to the excellent analgesic and anti-inflammatory response it has, important is knowing the pathophysiology of inflammation and pain, how NSAIDs act, some of these drugs have adverse responses and important sites of action, risk factors for inflammation and pain require us to know the variety of drugs that do not enter the classification of NSAIDs and we have at our disposal, there are more options for choosing in the presence of inflammation due to a particular factor, each of these have indications and contraindications that we will know, it expands our knowledge to give a prescription in the presence of inflammatory events. A detailed study of bibliographic articles on each topic was carried out, the drugs most used in dentistry are NSAIDs, there is little use and knowledge of anti-inflammatories that we can use in the emergency room, the percentage of use of NSAIDs derived from propionic acid is high, due to the excellent response in patients and others due to lack of knowledge of more options (AU)
Asunto(s)
Humanos , Masculino , Femenino , Odontalgia , Preparaciones Farmacéuticas , Antiinflamatorios no Esteroideos , Inflamación , Dolor/patología , Dolor Postoperatorio , Propionatos , Prostaglandinas/fisiología , Interacciones Farmacológicas , Ciclooxigenasa 1/farmacología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , NarcóticosRESUMEN
The activation of Nuclear Factor, Erythroid 2 Like 2 - Kelch Like ECH Associated Protein 1 (NRF2-KEAP1) signaling pathway plays a critical dual role by either protecting or promoting the carcinogenesis process. However, its activation or nuclear translocation during hepatocellular carcinoma (HCC) progression has not been addressed yet. This study characterizes the subcellular localization of both NRF2 and KEAP1 during diethylnitrosamine-induced hepatocarcinogenesis in the rat. NRF2-KEAP1 pathway was continuously activated along with the increased expression of its target genes, namely Nqo1, Hmox1, Gclc, and Ptgr1. Similarly, the nuclear translocation of NRF2, MAF, and KEAP1 increased in HCC cells from weeks 12 to 22 during HCC progression. Likewise, colocalization of NRF2 with KEAP1 was higher in the cell nuclei of HCC neoplastic nodules than in surrounding cells. Moreover, immunofluorescence analyses revealed that the interaction of KEAP1 with filamentous Actin was disrupted in HCC cells. This disruption may be contributing to the release and nuclear translocation of NRF2 since the cortical actin cytoskeleton serves as anchoring of KEAP1. In conclusion, this evidence indicates that NRF2 is progressively activated and promotes the progression of experimental HCC.
Asunto(s)
Carcinoma Hepatocelular/patología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Hepáticas/patología , Factor 2 Relacionado con NF-E2/metabolismo , Citoesqueleto de Actina/metabolismo , Animales , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/veterinaria , Núcleo Celular/metabolismo , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Dietilnitrosamina/toxicidad , Progresión de la Enfermedad , Proteína 1 Asociada A ECH Tipo Kelch/genética , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/veterinaria , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/genética , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-maf/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg-1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.
Asunto(s)
Antocianinas/uso terapéutico , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Estrés Oxidativo , Úlcera Péptica/complicaciones , Úlcera Péptica/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Ácido Acético , Animales , Antocianinas/farmacología , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Modelos Animales de Enfermedad , Duodeno/efectos de los fármacos , Duodeno/patología , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Etanol , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Regulación de la Expresión Génica/efectos de los fármacos , Indometacina , Inflamación/genética , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Úlcera Péptica/genética , Úlcera Péptica/inmunología , Polifarmacia , Sustancias Protectoras/farmacología , Daño por Reperfusión/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/genética , Úlcera Gástrica/inmunología , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Although crotoxin B (CB) is a well-established catalytically active secretory phospholipase A2 group IIA (sPLA2-IIA) myotoxin, we investigated its potential stimulatory effect on myogenesis with the involvement of prostaglandins (PGs) produced by cyclooxygenase (COX)-1 and -2 pathways. Myoblast C2C12 were cultured in proliferation or commitment protocols and incubated with CB followed by lumiracoxib (selective COX-2 inhibitor) or valeryl salicylate (selective COX-1 inhibitor) and subjected to analysis of PG release, cell proliferation and activation of myogenic regulatory factors (MRFs). Our data showed that CB in non-cytotoxic concentrations induces an increase of COX-2 protein expression and stimulates the activity of both COX isoforms to produce PGE2, PGD2 and 15d-PGJ2. CB induced an increase in the proliferation of C2C12 myoblast cells dependent on PGs from both COX-1 and COX-2 pathways. In addition, CB stimulated the activity of Pax7, MyoD, Myf5 and myogenin in proliferated cells. Otherwise, CB increased myogenin activity but not MyoD in committed cells. Our findings evidence the role of COX-1- and COX-2-derived PGs in modulating CB-induced activation of MRFs. This study contributes to the knowledge that CB promote early myogenic events via regulatory mechanisms on PG-dependent COX pathways, showing new concepts about the effect of sPLA2-IIA in skeletal muscle repair.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Crotoxina/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Fosfolipasas A2 Grupo II/farmacología , Proteínas de la Membrana/metabolismo , Desarrollo de Músculos/efectos de los fármacos , Mioblastos Esqueléticos/efectos de los fármacos , Neurotoxinas/farmacología , Prostaglandinas/metabolismo , Animales , Línea Celular , Ratones , Proteína MioD/metabolismo , Mioblastos Esqueléticos/enzimología , Factor 5 Regulador Miogénico/metabolismo , Miogenina/metabolismo , Factor de Transcripción PAX7/metabolismo , Transducción de SeñalRESUMEN
A case of abdominal dioctophymosis in a domestic cat was found in San Juan Bautista district, the Peruvian rainforest, in the Loreto department of Peru. The pet went to a veterinary clinic for a routine ovariohysterectomy during which a large nematode was found in the abdominal cavity. The nematode was morphologically identified as an adult female of Dioctophyme sp. A few morphological parameters, such as the vagina distance from the anterior part and the egg size, were different than D. renale. Partial sequences of the cytochrome c oxidase subunit I (cox1) and the small subunit 18S ribosomal RNA genes were compared with the references from public sequence database and showed a genetic identifies of 89.25% and 99.65% with D. renale, respectively. This is the first mitochondrial molecular analysis of a Dioctophyme specimen from South America and the results showed up to 12.5% nucleotide sequence variation in cox 1 gene of D. renale.
Asunto(s)
Enfermedades de los Gatos/parasitología , Dioctophymatoidea/aislamiento & purificación , Infecciones por Enoplida/veterinaria , Infecciones Intraabdominales/veterinaria , Animales , Enfermedades de los Gatos/diagnóstico , Gatos , Ciclooxigenasa 1/análisis , Dioctophymatoidea/clasificación , Infecciones por Enoplida/diagnóstico , Infecciones por Enoplida/parasitología , Femenino , Proteínas del Helminto/análisis , Infecciones Intraabdominales/diagnóstico , Infecciones Intraabdominales/parasitología , Perú , ARN de Helminto/análisis , ARN Ribosómico 18S/análisis , Bosque Lluvioso , Análisis de Secuencia de ADN/veterinaria , Análisis de Secuencia de ARN/veterinariaRESUMEN
OBJECTIVE: To investigate the main chemical components and the anti-inflammatory activity of extracts of Adelia ricinella L. aerial parts. METHODS: Three extracts obtained by soxhlet extraction and ethanol/water mixtures were evaluated in their chemical composition by UPLC-DAD-MS/MS. The in vitro anti-inflammatory activity of the prepared extracts was assessed through three different assays: COX-1 and COX-2 enzymatic inhibition, cell-based COX assays on RAW264.7 macrophages (ATCC) measuring the COX-2 protein expression by Western blot and the measurement of the PGE2 concentration in the supernatants of the culture medium. Also was determinate the effect of the three extracts on the RAW 264.7 cell viability. KEY FINDINGS: Few differences in the phytochemical profile were found between the three prepared extracts, identifying a blend of thirteen flavonoids derived from luteolin and apigenin, with orientin as main constituent. Plant extracts (alcoholic and aqueous) did not affect the macrophage cell viability (IC50 > 256 µg/ml) and significantly reduced COX-1 and COX-2 enzyme activities. Additionally, COX-2 expression and PGE2 release were suppressed after 24 h of LPS stimulation and treatment with plant extracts (8-64 µg/ml). CONCLUSIONS: A. ricinella extracts showed the ability to reduce the inflammatory effect exerted by LPS in murine macrophages. However, further studies should confirm their anti-inflammatory activity.
Asunto(s)
Apigenina , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Euphorbiaceae/química , Flavonoides , Glucósidos , Luteolina , Animales , Antiinflamatorios/farmacología , Apigenina/aislamiento & purificación , Apigenina/farmacología , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/análisis , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/análisis , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Glucósidos/aislamiento & purificación , Glucósidos/farmacología , Luteolina/aislamiento & purificación , Luteolina/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Componentes Aéreos de las Plantas , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7RESUMEN
Pulmonary arterial hypertension of the newborn (PAHN) is a syndrome caused by chronic hypoxia, characterized by decreased vasodilator function, a marked vasoconstrictor activity, proliferation of smooth muscle cells (SMC) and thickening of the extracellular matrix in the pulmonary circulation, among other characteristics. Prostaglandins are derived from the arachidonic acid (AA) metabolism and are important regulators of pulmonary vascular tone. Since hypoxia induces oxidative stress and has been related to PAHN, a postnatal treatment with melatonin has been proposed due to its antioxidant properties. Here, we determined the effects of melatonin on pulmonary vascular homeostasis given by prostanoids. Ten PAHN newborn lambs were divided in two groups and treated either with vehicle or melatonin. After 1 week of treatment, we assessed pulmonary vascular prostanoids function and expression by wire myography, RT-PCR, Western Blot and immunohistochemistry. Melatonin improved in vivo and ex vivo pulmonary vasodilation. This was associated with an increased function and expression of vasodilator prostanoids at the expense of vasoconstrictor prostanoids. Our study demonstrates for the first time that melatonin may enhance the vasodilator prostanoid pathway in PAHN.
Asunto(s)
Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Melatonina/farmacología , Prostaglandinas/metabolismo , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Animales Recién Nacidos , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Estrés Oxidativo/efectos de los fármacos , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Oveja Doméstica , Transducción de SeñalRESUMEN
BACKGROUND: In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential. METHODS: The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques. RESULTS: An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC50 of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC50 > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability. CONCLUSIONS: These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Tiosemicarbazonas/farmacología , Animales , Carragenina/farmacología , Celecoxib/farmacología , Proliferación Celular/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/metabolismo , Indoles/farmacología , Indometacina/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera (Less.) DC known as "carqueja" in Brazil has been acknowledged as a medicinal plant in folk medicine for the treatment of stomach aches and gastrointestinal disorders. AIM OF THE STUDY: The present study aimed to evaluate the gastroprotective and healing effects of essential oil from B. trimera (EOBT) against gastric ulcer lesions caused by absolute ethanol and acetic acid, respectively, and to identify the mechanism of action of this essential oil in male Wistar rats. MATERIALS AND METHODS: The plant material used to obtain EOBT was collected in the southern region of Brazil and was analyzed by chromatography-mass spectrometry (GCMS) demonstrate its characteristic chemical composition, with carquejyl acetate as its main component. Different doses of EOBT (50, 100, and 200 mg/kg) were administered orally in male Wistar rats as an acute treatment against absolute ethanol-induced gastric lesions. The gastric healing effect of EOBT (100 mg/kg) was evaluated once a day after 7, 10, and 14 days of treatment. After treatment, the stomachs of rats from all groups were collected to measure the lesion area (mm2), the activity of myeloperoxidase (MPO), and the relative expression of caspases -3, -8, -9, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). The zymography method was used to elucidate the activity of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in the healing action of EOBT. We also analyzed toxicological parameters (body weight evolution and biochemical parameters) that could result after treatment with this essential oil for 14 days. RESULTS: Pretreatment with EOBT (100 and 200 mg/kg) significantly decreased the severity of gastric damage induced by absolute ethanol and decreased MPO activity in gastric tissue. After 10 and 14 days of treatment with EOBT (100 mg/kg) once a day, the lesion area was significantly reduced by 61% and 65.5%, respectively, compared to the negative control group. The gastric healing effect of EOBT was followed by a decrease in the expression of COX-1 compared to that in the negative control group. Notably, treatment with EOBT for 14 days increased the expression of VEGF compared to that using an anti-ulcer drug (lansoprazole). Additionally, analyses of MMP-2 and MMP-9 activities in the gastric mucosa confirmed the accelerated gastric healing effect of EOBT, with a significant decrease in the activity of pro-MMP-2. No sign of toxicity was observed after treatment with EOBT for 14 consecutive days. CONCLUSION: These findings indicated that EOBT was effective in preventing and accelerating ulcer healing by decreasing MPO activity, increasing VEGF expression, and decreasing MMP-2 activity. These actions collectively contribute to the rapid recovery of gastric mucosa following treatment with EOBT, without any observed toxicity.
Asunto(s)
Antiulcerosos/farmacología , Baccharis/química , Metaloproteinasa 2 de la Matriz/metabolismo , Aceites Volátiles/farmacología , Úlcera Gástrica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ácido Acético/toxicidad , Animales , Antiulcerosos/uso terapéutico , Antiulcerosos/toxicidad , Brasil , Caspasas/metabolismo , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Etanol/toxicidad , Mucosa Gástrica/efectos de los fármacos , Lansoprazol/farmacología , Lansoprazol/uso terapéutico , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Medicina Tradicional , Proteínas de la Membrana/metabolismo , Aceites Volátiles/uso terapéutico , Aceites Volátiles/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologíaRESUMEN
The presence of four sharks was documented in coastal waters of Antofagasta (Chile) using an unmanned aerial video camera. Fishers took advantage of this aggregation to catch and sold three adult broadnose sevengill sharks Notorynchus cepedianus. Species identity was determined by using the cox1 gene. One additional video was later recorded 3000 km south of Antofagasta, and shows a large female interacting with a salmon farming facility. Shallow water records of N. cepedianus were previously undocumented in Chilean waters, yet historically have provided an opportunistic event to fishers in Chile.
Asunto(s)
Distribución Animal , Explotaciones Pesqueras , Tiburones/fisiología , Animales , Chile , Ciclooxigenasa 1/genética , Femenino , Explotaciones Pesqueras/tendencias , Océano Pacífico , Grabación en VideoRESUMEN
Solidagenone (SOL) is a labdane-type diterpenoid found in Solidago chilensis, a plant traditionally used to treat skin diseases, kidney pain and ovarian inflammation. In this study, the topical anti-inflammatory activity of SOL was evaluated using in vivo and in silico assays. Croton oil-, arachidonic acid (AA)- and phenol-induced ear oedema mouse models were applied in the in vivo studies. Myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAG) activities and tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) levels were determined, as well as histopathological analyses were conducted. Interaction profiles between SOL and cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), glucocorticoid receptor, estradiol-17-ß-dehydrogenase and prostaglandin-E(2)-9-reductase were established using molecular docking. SOL significantly inhibited croton oil-, AA- and phenol-induced ear oedema (P < .001) at doses of 0.1, 0.5 and 1.0 mg/ear. The MPO and NAG activities and TNF-α, IL-6 and NO levels were decreased (P < .001). The histopathological data revealed that inflammatory parameters (oedema thickness, leucocyte infiltration and vasodilatation) were reduced by treatment with SOL at doses of 0.1, 0.5 and 1.0 mg/ear. The docking study showed that SOL interacts with COX-1 and prostaglandin-E(2)-9-reductase through hydrogen bonding, inhibiting these enzymes. These results indicate that SOL may be a promising compound for the treatment of cutaneous inflammatory disorders and has potential as a topical anti-inflammatory agent.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Dermatitis/prevención & control , Edema/prevención & control , Furanos/farmacología , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Naftalenos/farmacología , Extractos Vegetales/farmacología , Piel/efectos de los fármacos , Solidago , Acetilglucosaminidasa/metabolismo , Animales , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa/aislamiento & purificación , Inhibidores de la Ciclooxigenasa/metabolismo , Dermatitis/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/metabolismo , Edema/patología , Furanos/aislamiento & purificación , Furanos/metabolismo , Enlace de Hidrógeno , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Interleucina-6/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Naftalenos/aislamiento & purificación , Naftalenos/metabolismo , Óxido Nítrico/metabolismo , Peroxidasa/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Unión Proteica , Transducción de Señal , Piel/metabolismo , Piel/patología , Solidago/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Sesquiterpene lactones (SL) are natural bioactive molecules indicated as potential scaffolds for anti-inflammatory and analgesic drug design. However, their anti-inflammatory applicability remains underestimated since the impact of SL on inflammatory nociception and tissue repair are overlooked. Thus, we used an integrated in silico, in vitro and in vivo framework to investigate the impact of tagitinin F (TAG-F) on lipopolysaccharide (LPS)-challenged macrophages, excisional skin wounds, and carrageenan-induced paw edema and mechanical hyperalgesia in mice. RAW 264.7 macrophages in culture were challenged with LPS and treated with TAG-F (5, 10, 50 and 100 µM). The paw of BALB/c mice was injected with carrageenan and treated with 0.5% and 1% TAG-F. Excisional wounds were also produced in BALB/c mice and treated with 0.5% and 1% TAG-F. Our results indicated a consistent concentration-dependent downregulation in 5-lipoxygenase, cyclooxygenase 1 and 2 (COX-1 and COX-2), matrix metalloproteinase 1 and 2 (MMP-1 and MMP-2) activities; as well as attenuation in prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and tumor necrosis factor-α (TNF-α) production in both in vitro and in vivo models. In vivo, TAG-F also attenuated carrageenan-induced paw edema and mechanical hyperalgesia in mice. From the excisional skin wound, TAG-F was still effective in reducing neutrophils and macrophages infiltration and stimulating collagen deposition in the scar tissue, accelerating tissue maturation. Together, our findings indicate that the anti-inflammatory effect of TAG-F is more comprehensive than previously suggested, exerting a significant impact on the control of edema, inflammatory pain and modulating central metabolic processes linked to skin wound healing.
Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Cicatriz/tratamiento farmacológico , Edema/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Carragenina , Cicatriz/metabolismo , Colágeno/metabolismo , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Edema/inducido químicamente , Leucotrieno B4/metabolismo , Lipopolisacáridos/farmacología , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Células RAW 264.7 , Sesquiterpenos/farmacología , Tacto , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Chronic inflammation is triggered by numerous diseases such as osteoarthritis, Crohn's disease and cancer. The control of the pro-inflammatory process can prevent, mitigate and/or inhibit the evolution of these diseases. Therefore, anti-inflammatory drugs have been studied as possible compounds to act in these diseases. This paper proposes a computational analysis of eugenol in relation to aspirin and diclofenac and analyzing the ADMET profile and interactions with COX-2 and 5-LOX enzymes, important enzymes in the signaling pathway of pro-inflammatory processes. Through the analysis of ADMET in silico, it was found that the pharmacokinetic results of eugenol are similar to NSAIDs, such as diclofenac and aspirin. Bioinformatics analysis using coupling tests showed that eugenol can bind to COX-2 and 5-LOX. These results corroborate with different findings in the literature that demonstrate anti-inflammatory activity with less gastric irritation, bleeding and ulcerogenic side effects of eugenol. The results of bioinformatics reinforce studies that try to propose eugenol as an anti-inflammatory compound that can act in the COX-2/5-LOX pathways, replacing some NSAIDs in different diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Biología Computacional/métodos , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Eugenol/metabolismo , Lipooxigenasa/metabolismo , Antiinfecciosos/química , Antiinfecciosos/metabolismo , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Antiinflamatorios no Esteroideos/química , Ciclooxigenasa 1/química , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Eugenol/química , Humanos , Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
CONTEXT: Cancer Pain is considered a common and significant clinical problem in malignant neoplasms, comprising 20% to 50% of all patients with tumor progression. Laser photobiomodulation (L-PBM) has been used in a multitude of pain events, ranging from acute trauma to chronic articular. However, L-PBM has never been tested in cancer pain. OBJECTIVES: Evaluate hyperalgesia, edema, COX-1, COX-2, IL-10, and Bdkrb1 mRNA in low-level laser irradiated Walker-256 tumor-bearing rats. METHODS: Rat hind paw injected with Walker Tumor-256 (W-256) and divided into six groups of 6 rats: G1 (control) - W-256 injected, G2- W-256â¯+â¯Nimesulide, G3- W-256â¯+â¯1â¯J, G4- W-256â¯+â¯3â¯Jand G5- W256â¯+â¯6â¯J. Laser parameters: λâ¯=â¯660â¯nm, 3.57â¯W/cm2, Øâ¯=â¯0.028â¯cm2. Mechanical hyperalgesia was evaluated by Randall-Selitto test. Plethysmography measured edema; mRNA levels of COX-1, COX-2, IL-10, and Bdkrb1were analyzed. RESULTS: It was found that the W-256â¯+â¯1â¯J group showed a decrease in paw edema, a significant reduction in pain threshold. Higher levels of IL-10 and lower levels of COX-2 and Bdkrb1 were observed. CONCLUSION: Results suggest that 1â¯Jâ¯L-PBM reduced the expression of COX-2 and Bdkrb1 and increasing IL-10 gene expression, promoting analgesia to close levels to nimesulide.
Asunto(s)
Hiperalgesia/radioterapia , Láseres de Semiconductores/uso terapéutico , Terapia por Luz de Baja Intensidad , Animales , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patología , Línea Celular Tumoral , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Edema/metabolismo , Edema/patología , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Pletismografía , Ratas , Ratas Wistar , Trasplante HeterólogoRESUMEN
BACKGROUND: The blood-feeding behaviour of female sand flies may increase their likelihood of acquiring and transmitting Leishmania parasites. Studies on the host usage by these insects may thus improve our understanding of the Leishmania transmission risk in leishmaniasis-endemic areas. Here, we developed a fast multiplex real-time PCR assay for simultaneous detection of dog, human and Leishmania DNA in sand flies. METHODS: Primers and TaqMan probes targeting the mitochondrial cytochrome c oxidase subunit 1 and cytochrome b genes of dog and human, respectively, were combined in a multiplex assay, which also includes primers and a TaqMan probe targeting the Leishmania minicircle kinetoplast DNA. RESULTS: The multiplex assay was 100% specific, with analytical sensitivities of 103 fg/reaction for dog and human and 1 fg for Leishmania. By testing field-collected engorged female sand flies (95 Migonemyia migonei and two Nyssomyia intermedia), 50 M. migonei were positive for one or two targets (positivity rates: 45.4% for human, 4.1% for dog and 12.4% for Leishmania DNA). CONCLUSIONS: This multiplex real-time PCR assay represents a novel fast assay for detecting dog, human and Leishmania DNA in female sand flies and therefore a tool for assessing the risk of Leishmania transmission to these hosts in areas of active transmission.
Asunto(s)
Leishmania/genética , Leishmaniasis/diagnóstico , Leishmaniasis/veterinaria , Reacción en Cadena de la Polimerasa Multiplex/métodos , Psychodidae/parasitología , Animales , Ciclooxigenasa 1/genética , Cartilla de ADN/genética , ADN de Cinetoplasto/genética , Perros , Femenino , Humanos , Proteínas de Insectos/genética , Insectos Vectores/parasitología , Leishmaniasis/transmisión , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
Being the base of several non-communicable diseases, including cancer, inflammation is a complex process generated by tissue damage or change in the body homeostatic state. Currently, the therapeutic treatment for chronic inflammation related diseases is based on the use of selective cyclooxygenase II enzyme, COX-2, inhibitors or Coxibs, which have recently regained attention giving their preventive role in colon cancer. Thus, the discovery of new molecules that selectively inhibit COX-2 and other inflammatory mediators is a current challenge in the medicinal chemistry field. 1-Phenylbenzimidazoles have shown potential COX inhibitory activity, because they can reproduce the interaction profile of known COX inhibitors. Therefore, in the present investigation a series of 1,2-diphenylbenzimidazoles (DPBI) with different aromatic substitutions in the para position were synthesized and their interaction with COX-2 and nitric oxide synthase, iNOS, was determined in silico, in vitro and in vivo. Compound 2-(4-bromophenyl)-1-(4-nitrophenyl)-1H-benzo[d]imidazole showed the best inhibition towards COX-2, while compounds N-(4-(2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide and N-(4-(2-(4-chlorophenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide diminished the production of NO in vitro. Additionally, they had a significant anti-inflammatory activity in vivo when given orally.